tbuckley/cabot-search huggingface dataset:
Treatments During Pregnancy Targeting ERBB2 and Outcomes of Pregnant Individuals and Newborns
Authors: Paul Gougis, Beatriz Grandal, Floriane Jochum, Kevin Bihan, Florence Coussy, Solenn Barraud, Bernard Asselain, Elise Dumas, Clara Sebbag, Judicael Hotton, Emmanuel Spaggiari, Jean-Yves Pierga, Raphaëlle Savarino, Enora Laas, Jean-Philippe Spano, Fabien Reyal, Anne-Sophie Hamy
Journal: JAMA Network Open (2023)

Importance Targeted therapies directed against ERBB2 are the cornerstone of medical treatment for ERBB2-positive breast cancers but are contraindicated during pregnancy. Objectives To describe the association of exposure to anti-ERBB2 agents during pregnancy with pregnancy and fetal or newborn outcomes, and to compare the risk and types of adverse outcomes reported more frequently in this context than after exposure to other anticancer agents. Design, Setting, and Participants For this case-control study, All reports with a pregnancy-related condition and an antineoplastic agent (Anatomical Therapeutic Chemical classification group L01) registered in the World Health Organization international pharmacovigilance database VigiBase up to June 26, 2022, were extracted. All reports with a pregnancy, an antineoplastic treatment during pregnancy, and a cancer were retained. Reports with anticancer agents prescribed for nononcologic purposes were not included. Exposure The exposure group was defined as reports that mention anti-ERBB2 agents compared with exposure to other anticancer agents. Main Outcome and Measures The main outcome was the reporting odds ratio (ROR) for maternofetal complications in the group exposed to anti-ERBB2 agents compared with other anticancer agents, as determined using a disproportionality analysis. Results A total of 3558 reports (anti-ERBB2 agents, 328; other anticancer agents, 3230) were included in the analysis. In the group exposed to anti-ERBB2 agents, most reports were from the US (159 [48.5%]), the mean (SD) age of participants was 30.8 (10.4) years, and 209 patients (97.7%) were treated for breast cancers. The molecules most frequently involved in cases with anti-ERBB2 agents were trastuzumab (n = 302), pertuzumab (n = 55), trastuzumab-emtansine (n = 20), and lapatinib (n = 18). The outcomes overreported in these cases included oligohydramnios (ROR, 17.68 [95% CI, 12.26-25.52]; P &amp;amp;lt; .001), congenital respiratory tract disorders (ROR, 9.98 [95% CI, 2.88-34.67]; P &amp;amp;lt; .001), and neonatal kidney failure (ROR, 9.15 [95% CI, 4.62-18.12]; P &amp;amp;lt; .001). Sensitivity and multivariable analyses found similar results. Toxic effects were also significantly overreported for trastuzumab-emtansine (cardiovascular malformation: ROR, 4.46 [95% CI, 1.02-19.52]) and lapatinib (intrauterine growth restriction: ROR, 7.68 [95% CI, 3.01-19.59]). Conclusions and Relevance In this case-control study of 328 individuals exposed to anti-ERBB2 agents during pregnancy, exposure was associated with a severe specific adverse pregnancy and fetal or newborn outcomes compared with exposure to other anticancer treatments.
Ceftriaxone and the Risk of Ventricular Arrhythmia, Cardiac Arrest, and Death Among Patients Receiving Lansoprazole
Authors: Anthony D. Bai, Amelia Wilkinson, Aws Almufleh, Mandip Rai, Fahad Razak, Amol A. Verma, Siddhartha Srivastava
Journal: JAMA Network Open (2023)

Importance The combination of ceftriaxone and lansoprazole has been shown to prolong the corrected QT interval on electrocardiogram. However, it is unknown whether this translates to clinically important patient outcomes. Objective To compare lansoprazole with another proton pump inhibitor (PPI) during ceftriaxone treatment in terms of risk for ventricular arrhythmia, cardiac arrest, and in-hospital mortality. Design, Setting, and Participants A retrospective cohort study including adult medical inpatients receiving ceftriaxone with lansoprazole or another PPI in 13 hospitals in Ontario, Canada, was conducted from January 1, 2015, to December 31, 2021. Exposure Lansoprazole during ceftriaxone treatment vs other PPIs during ceftriaxone treatment. Main Outcomes and Measures The primary outcome was a composite of ventricular arrhythmia or cardiac arrest that occurred after hospital admission. The secondary outcome was all-cause in-hospital mortality. Propensity-score weighting was used to adjust for covariates including hospital site, demographic characteristics, comorbidities, risk factors for ventricular arrhythmia, illness severity, admitting diagnoses, and concomitant medications. Results Of the 31 152 patients hospitalized on internal medicine wards who were treated with ceftriaxone while receiving a PPI, 16 135 patients (51.8%) were male, and the mean (SD) age was 71.7 (16.0) years. The study included 3747 patients in the lansoprazole group and 27 405 patients in the other PPI group. Ventricular arrhythmia or cardiac arrest occurred in 126 patients (3.4%) within the lansoprazole group and 319 patients (1.2%) within the other PPI group. In-hospital mortality occurred in 746 patients (19.9%) within the lansoprazole group and 2762 patients (10.1%) in the other PPI group. After weighting using propensity scores, the adjusted risk difference for the lansoprazole group minus other PPI group was 1.7% (95% CI, 1.1%-2.3%) for ventricular arrhythmia or cardiac arrest and 7.4% (95% CI, 6.1%-8.8%) for in-hospital mortality. Conclusions and Relevance The findings of this cohort study suggest that combination therapy with lansoprazole and ceftriaxone should be avoided. More studies are needed to determine whether these findings could be replicated in other populations and settings.
Prenatal Zika virus infection has sex-specific effects on infant physical development and mother-infant social interactions
Authors: Gilda Moadab, Florent Pittet, Jeffrey L. Bennett, Christopher L. Taylor, Olivia Fiske, Anil Singapuri, Lark L. Coffey, Koen K. A. Van Rompay, Eliza Bliss-Moreau
Journal: Science Translational Medicine (2023)

There is enormous variation in the extent to which fetal Zika virus (fZIKV) infection affects the developing brain. Despite the neural consequences of fZIKV infection observed in people and animal models, many open questions about the relationship between infection dynamics and fetal and infant development remain. To further understand how ZIKV affects the developing nervous system and the behavioral consequences of prenatal infection, we adopted a nonhuman primate model of fZIKV infection in which we inoculated pregnant rhesus macaques and their fetuses with ZIKV in the early second trimester of fetal development. We then tracked their health across gestation and characterized infant development across the first month of life. ZIKV-infected pregnant mothers had long periods of viremia and mild changes to their hematological profiles. ZIKV RNA concentrations, an indicator of infection magnitude, were higher in mothers whose fetuses were male, and the magnitude of ZIKV RNA in the mothers' plasma or amniotic fluid predicted infant outcomes. The magnitude of ZIKV RNA was negatively associated with infant growth across the first month of life, affecting males' growth more than females' growth, although for most metrics, both males and females evidenced slower growth rates as compared with control animals whose mothers were not ZIKV inoculated. Compared with control infants, fZIKV infants also spent more time with their mothers during the first month of life, a social behavior difference that may have long-lasting consequences on psychosocial development during childhood.
Long-Term Results of Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy: The Randomized Phase II OPRA Trial
Authors: Floris S. Verheij, Dana M. Omer, Hannah Williams, Sabrina T. Lin, Li-Xuan Qin, James T. Buckley, Hannah M. Thompson, Jonathan B. Yuval, Jin K. Kim, Richard F. Dunne, Jorge Marcet, Peter Cataldo, Blase Polite, Daniel O. Herzig, David Liska, Samuel Oommen, Charles M. Friel, Charles Ternent, Andrew L. Coveler, Steven Hunt, Anita Gregory, Madhulika G. Varma, Brian L. Bello, Joseph C. Carmichael, John Krauss, Ana Gleisner, José G. Guillem, Larissa Temple, Karyn A. Goodman, Neil H. Segal, Andrea Cercek, Rona Yaeger, Garrett M. Nash, Maria Widmar, Iris H. Wei, Emmanouil P. Pappou, Martin R. Weiser, Philip B. Paty, J. Joshua Smith, Abraham J. Wu, Marc J. Gollub, Leonard B. Saltz, Julio Garcia-Aguilar
Journal: Journal of Clinical Oncology (2023)

JCO
Long-Term Follow-Up of the Response-Adjusted Therapy for Advanced Hodgkin Lymphoma Trial
Authors: Stefano Luminari, Alexander Fossa, Judith Trotman, Daniel Molin, Francesco d'Amore, Gunilla Enblad, Leanne Berkahn, Sally F. Barrington, John Radford, Massimo Federico, Amy A. Kirkwood, Peter W.M. Johnson
Journal: Journal of Clinical Oncology (2023)

JCO
Open-Label, Multicenter, Randomized, Biomarker-Integrated Umbrella Trial for Second-Line Treatment of Advanced Gastric Cancer: K-Umbrella Gastric Cancer Study
Authors: Choong-kun Lee, Hyo Song Kim, Minkyu Jung, Hyunki Kim, Woo Kyun Bae, Dong-Hoe Koo, Hei Cheul Jeung, Sook Ryun Park, In Gyu Hwang, Dae Young Zang, Hyun Woo Lee, Sejung Park, Chung Mo Nam, Hyun Cheol Chung, Sun Young Rha
Journal: Journal of Clinical Oncology (2023)

This study aimed to screen targeted agents as second-line treatment with a standard-of-care (SOC) controlled umbrella trial design in advanced gastric cancer (AGC).
Survival Trends Among Adolescents and Young Adults Diagnosed With Cancer in the United States: Comparisons With Children and Older Adults
Authors: Theresa H.M. Keegan, Renata Abrahão, Elysia M. Alvarez
Journal: Journal of Clinical Oncology (2023)

Although data from 1975 to 1997 revealed a gap in cancer survival improvement in adolescents and young adults (AYAs; 15-39 years) compared with children and older adults, more recent studies have reported improvements in AYA cancer survival overall. The current analysis provides an update of 5-year relative survival and cancer survival trends among AYAs compared with children and older adults.
An Erythrocyte Membrane‐Derived Nanosystem for Efficient Reversal of Endothelial Injury in Sepsis
Authors: Yao Zhang, Jian Li, Qi Jing, Ziying Chen, Kai Wang, Chuanzheng Sun
Journal: Advanced Healthcare Materials (2023)

Abstract Sepsis is caused by a disordered host immune in response to infection and endothelial cells perform a crucial role in boosting immunity reaction in the pathophysiology of sepsis and septic organ failure. The aim of this study is to construct a novel erythrocyte membrane‐derived nanosystems to reverse endothelial damage in sepsis. Herein, an innovative nanometer calcium metal‐organic framework (Ca‐MOF) is generated for the first time by using chelidonic acid as a ligand and calcium chloride as an ion donor for anti‐inflammation. Then, zoliflodacin is loaded into Ca‐MOF (CMZ) to sterilize and nanoscale erythrocyte membrane vesicles are prepared by modification with a γ3 peptide on the surface (γ3‐RM) for precise targeting. Finally, γ3‐RM camouflages the nanocore CMZ, to form novel erythrocyte membrane‐camouflaged nanoparticle γ3‐RCMZ. The superior performance of novel nanosystem results from its suitable biocompatibility, nontoxicity, specific targeting, and anti‐inflammatory and bactericidal effects. Its anti‐inflammatory mechanism mainly involves inhibiting the Caspase1‐nuclear factor kappa‐B (Caspase1‐NF‐κB) pathway and oxidative stress reduction to alleviate endothelial damage. Moreover, the findings have revealed for the first time that the bactericidal drug zoliflodacin also has anti‐inflammatory effects in vivo and in vitro. Therefore, the novel nanosystem (γ3‐RCMZ) provides a new nanotherapy strategy for sepsis treatment.
Correction to: CTLA-4 Pathway Is Instrumental in Giant Cell Arteritis
Journal: Circulation Research (2023)

a correction was needed."Although Tregs from GCA show a suppressive phenotype, the remaining activated CTLA-4+ Ki-67+ Tregs are highly sensitive to anti-CTLA-4-mediated in vitro depletion" in the Novelty and Significance section should be updated to read: "Although Tregs from GCA show a less suppressive phenotype, the remaining activated CTLA-4+ Ki-67+ Tregs are highly sensitive to anti-CTLA-4-mediated in vitro depletion."A subheading in the Results section should be updated from "Despite Being Suppressive, Circulating Tregs Overexpress CTLA-4 in GCA" to "Despite Being Less Suppressive, Circulating Tregs Overexpress
Shear Force-Induced Platelet Clearance Is a New Mechanism of Thrombocytopenia
Authors: Antoine Rauch, Annabelle Dupont, Mickael Rosa, Maximilien Desvages, Christina Le Tanno, Johan Abdoul, Mélusine Didelot, Alexandre Ung, Richard Ruez, Emmanuelle Jeanpierre, Mélanie Daniel, Delphine Corseaux, Hugues Spillemaeker, Julien Labreuche, Bénédicte Pradines, Natacha Rousse, Peter J. Lenting, Mouhamed D. Moussa, André Vincentelli, Jean-Claude Bordet, Bart Staels, Flavien Vincent, Cécile V. Denis, Eric Van Belle, Caterina Casari, Sophie Susen
Journal: Circulation Research (2023)

Thrombocytopenia has been consistently described in patients with extracorporeal membrane oxygenation (ECMO) and associated with poor outcome. However, the prevalence and underlying mechanisms remain largely unknown, and a device-related role of ECMO in thrombocytopenia has been hypothesized. This study aims to investigate the mechanisms underlying thrombocytopenia in ECMO patients.
The role of N-glycosylation in cancer
Authors: Yu Lin, David M. Lubman
Journal: Acta Pharmaceutica Sinica B (2023)

Despite advances in understanding the development and progression of cancer in recent years, there remains a lack of comprehensive characterization of the cancer glycoproteome. Glycoproteins play an important role in medicine and are involved in various human disease conditions including cancer. Glycan-moieties participate in fundamental cancer processes like cell signaling, invasion, angiogenesis, and metastasis. Aberrant
Two types of coumarins-specific enzymes complete the last missing steps in pyran- and furanocoumarins biosynthesis
Authors: Yucheng Zhao, Yuedong He, Liangliang Han, Libo Zhang, Yuanzheng Xia, Fucheng Yin, Xiaobing Wang, Deqing Zhao, Sheng Xu, Fei Qiao, Yibei Xiao, Lingyi Kong
Journal: Acta Pharmaceutica Sinica B (2023)

Pyran- and furanocoumarins are key representatives of tetrahydropyrans and tetrahydrofurans, respectively, exhibiting diverse physiological and medical bioactivities. However, the biosynthetic mechanisms for their core remain poorly understood. Here we combined multiomics analyses of biosynthetic enzymes in Peucedanum praeruptorum and in vitro functional verification and identified two types of key enzymes critical for pyran and furan ring biosynthesis in plants. These included three distinct P. praeruptorum prenyltransferases (PpPT1–3) responsible for the prenylation of the simple coumarin skeleton 7 into linear or angular precursors, and two novel CYP450 cyclases (PpDC and PpOC) crucial for the cyclization of the linear/angular precursors into either tetrahydropyran or tetrahydrofuran scaffolds. Biochemical analyses of cyclases indicated that acid/base-assisted epoxide ring opening contributed to the enzyme-catalyzed tetrahydropyran and tetrahydrofuran ring refactoring. The possible acid/base-assisted catalytic mechanisms of the identified cyclases were theoretically investigated and assessed using site-specific mutagenesis. We identified two possible acidic amino acids Glu303 in PpDC and Asp301 in PpOC as vital in the catalytic process. This study provides new enzymatic tools in the epoxide formation/epoxide-opening mediated cascade reaction and exemplifies how plants become chemically diverse in terms of enzyme function and catalytic process.
Prevalence and variability of depressive symptoms in Europe: update using representative data from the second and third waves of the European Health Interview Survey (EHIS-2 and EHIS-3)
Authors: Jorge Arias-de la Torre, Gemma Vilagut, Amy Ronaldson, Ioannis Bakolis, Alex Dregan, Vicente Martín, Gonzalo Martinez-Alés, Antonio J Molina, Antoni Serrano-Blanco, Jose M Valderas, Maria Carmen Viana, Jordi Alonso
Journal: The Lancet Public Health (2023)

BackgroundAssessing the prevalence of clinically relevant depressive symptoms and their possible variation by country and over time could be a valuable resource to inform the development of public health policies and preventive resources to reduce mental health burden. We aimed to assess cross-national differences in the point prevalence of clinically relevant depressive symptoms in Europe in 2018–20, and to evaluate point prevalence differences between countries and over time between 2013–15 and 2018–20.MethodsIn this population-based study, data from participants in the second and third waves of the European Health Interview Survey (EHIS-2 from 2013 to 2015 and EHIS-3 from 2018 to 2020) from 30 European countries were used (n=542 580). From the total sample, 283 692 participants belonging to EHIS-3 were included in the study (52·4% women and 47·5% men). The non-response in EHIS-3 ranged by country, from 12% to 78%. Point prevalence of clinically relevant depressive symptoms was evaluated using a cutoff score of 10 or more for the 8-item version of the Patient Health Questionnaire. Crude prevalence ratios and adjusted prevalence ratios (aPRs) were obtained to assess differences in the prevalence between countries and over time within countries.FindingsThe point prevalence of clinically relevant depressive symptoms in Europe in 2018–20 was 6·54% (95% CI 6·34–6·73), ranging across countries from 1·85% (1·53–2·17) in Greece to 10·72% (10·04–11·40) in Sweden. Compared with the other European countries, those with the lowest aPRs were Greece, Serbia, and Cyprus and those with the highest aPRs were Belgium, Slovenia, and Croatia. A small but significant increase in the prevalence between EHIS-2 and EHIS-3 was observed (aPR 1·11 [1·07–1·14]). A wide variability over time in the point prevalence within countries was observed, ranging from an aPR of 0·63 (0·54–0·74) in Hungary to 1·88 (1·53–2·31) in Slovenia.InterpretationThis study, based on large and representative datasets and a valid and reliable screening tool for the assessment of depression, indicates that the point prevalence of clinically relevant depressive symptoms in Europe from 2013 to 2020 remains relatively stable, with wide variability between countries. These findings could be considered a baseline for monitoring the prevalence of clinically relevant depressive symptoms in Europe, and could inform policy for the development of preventive strategies for depression both at a country and European level.FundingCenter for Biomedical Research in Epidemiology and Public Health Network and AGAUR.
Anti-PF4 immunothrombosis without proximate heparin or adenovirus vector vaccine exposure
Authors: Linda Schönborn, Olga Esteban, Jan Wesche, Paulina Dobosz, Marta Broto, Sara Rovira Puig, Jessica Fuhrmann, Raquel Torres, Josep Serra, Roser Llevadot, Marta Palicio, Jing Jing Wang, Tom Paul Gordon, Edelgard Lindhoff-Last, Till Hoffmann, Lorenzo Alberio, Florian Langer, Christian Boehme, Eugenia Biguzzi, Leonie Grosse, Matthias Endres, Thomas Liman, Thomas Thiele, Theodore E. Warkentin, Andreas Greinacher
Journal: Blood (2023)

Platelet-activating anti-platelet factor 4 (PF4)/heparin antibodies and anti-PF4 antibodies cause heparin-induced thrombocytopenia (HIT) and vaccine-induced immune thrombocytopenia and thrombosis (VITT), respectively. Diagnostic and treatment considerations differ somewhat between HIT and VITT. We identified patients with thrombocytopenia and thrombosis without proximate heparin exposure or adenovirus-based vaccination who tested strongly positive by PF4/polyanion enzyme-immunoassays and negative/weakly positive by heparin-induced platelet activation (HIPA) test but strongly positive by PF4-induced platelet activation (PIPA) test (ie, VITT-like profile). We tested these patients by a standard chemiluminescence assay that detects anti-PF4/heparin antibodies found in HIT (HemosIL AcuStar HIT-IgG(PF4-H)) as well as a novel chemiluminescence assay for anti-PF4 antibodies found in VITT. Representative control sera included an exploratory anti-PF4 antibody-positive but HIPA-negative/weak cohort obtained before 2020 (n = 188). We identified 9 patients with a clinical-pathological profile of a VITT-like disorder in the absence of proximate heparin or vaccination, with a high frequency of stroke (arterial, n = 3; cerebral venous sinus thrombosis, n = 4), thrombocytopenia (median platelet count nadir, 49 × 109/L), and hypercoagulability (greatly elevated D-dimer levels). VITT-like serological features included strong reactivity by PIPA (aggregation <10 minutes in 9/9 sera) and positive testing in the novel anti-PF4 chemiluminescence assay (3/9 also tested positive in the anti-PF4/heparin chemiluminescence assay). Our exploratory cohort identified 13 additional patient sera obtained before 2020 with VITT-like anti-PF4 antibodies. Platelet-activating VITT-like anti-PF4 antibodies should be considered in patients with thrombocytopenia, thrombosis, and very high D-dimer levels, even without a proximate exposure to heparin or adenovirus vector vaccines.
PF4 activates the c-Mpl–Jak2 pathway in platelets
Authors: Richard J. Buka, Samantha J. Montague, Luis A. Moran, Eleyna M. Martin, Alexandre Slater, Steve P. Watson, Phillip L. R. Nicolson
Journal: Blood (2023)

Abstract Platelet factor 4 (PF4) is an abundant chemokine that is released from platelet α-granules on activation. PF4 is central to the pathophysiology of vaccine-induced immune thrombocytopenia and thrombosis (VITT) in which antibodies to PF4 form immune complexes with PF4, which activate platelets and neutrophils through Fc receptors. In this study, we show that PF4 binds and activates the thrombopoietin receptor, cellular myeloproliferative leukemia protein (c-Mpl), on platelets. This leads to the activation of Janus kinase 2 (JAK2) and phosphorylation of signal transducer and activator of transcription (STAT) 3 and STAT5, leading to platelet aggregation. Inhibition of the c-Mpl–JAK2 pathway inhibits platelet aggregation to PF4, VITT sera, and the combination of PF4 and IgG isolated from VITT patient plasma. The results support a model in which PF4-based immune complexes activate platelets through binding of the Fc domain to FcγRIIA and PF4 to c-Mpl.
CAR T cells and time-limited ibrutinib as treatment for relapsed/refractory mantle cell lymphoma: the phase 2 TARMAC study
Authors: Adrian Minson, Nada Hamad, Chan Y. Cheah, Constantine Tam, Piers Blombery, David Westerman, David Ritchie, Huw Morgan, Nicholas Holzwart, Stephen Lade, Mary Ann Anderson, Amit Khot, John F. Seymour, Molly Robertson, Imogen Caldwell, Georgina Ryland, Javad Saghebi, Zahra Sabahi, Jing Xie, Rachel Koldej, Michael Dickinson
Journal: Blood (2023)